Evidence has accumulated that digitalis-like factors (EDLF) may play an important role in the pathogenesis of cardiovascular disease (hypertension, congestive heart failure, acute myocardial infarction) via their ability to inhibit sodium pump activity. Much attention has been paid to one of these factors, an endogenous ouabain; however, a digoxin-like immunoreactive factor has also been found previously to contribute to arrythmogenesis in myocardial ischemia. The objectives of this project are to clarify the role of various sodium pump inhibitors, especially the digoxin-like immunoreactive EDLF, in blood pressure regulation. Over the past year, studies have been performed with instrumented dogs whose plasma volume was expanded via saline infusion. Increases in plasma and urinary EDLF evoked by this procedure were associated with increases in cardiac contractility, urinary sodium excretion, and variable increases in blood pressure. Pretreatment of the animals with an antidigoxin antibody prevented or attenuated these effects. Effects of sodium pump inhibitors on vascular tone and vascular sodium pump activity in rat aortas and dog femoral arteries were studied in vitro. Compared with the effects of ouabain, EDLF obtained from the venom of Bufo marinus toad caused direct inhibition of sodium pump resulting in rapid and sustained vasoconstriction. Unlike ouabain, this EDLF acted independently of the sympathetic nervous system. These studies have implications for understanding of the origins of hypertension and for the development of new pharmacological interventions in cardiovascular disorders.